This study is designed to confirm or disconfirm hypotheses regarding biochemical and neuroendocrinological mechanisms in the etiology and maintenance of depression and mania. Particular emphasis is given to the possibility that the genesis of affective disturbances may involve an interaction between or among biological systems, such as serotonergic and noradrenergic. In addition to biochemical assays reflective of aminergic systems, intensive study of hypothalamic-pituitary-adrenocortical systems, cyclic AMP and serum magnesium will also be undertaken. Blood metabolites of amitriptyl and imipramine will be assayed. Detailed, systematic behavioral ratings will allow exploration of behavioral-biological interactions and serve to better define clinical and biological subgroups of affective disorders. A unique and key aspect of the study is the collaboration of a number of geographically separate groups of investigators. The individual but synthesized expertise of the investigators may serve as a model for subsequent collaborative studies. An ongoing review mechanism allows incorporation into the research protocol of new techniques or hypotheses, as well as deletion of studies as hypotheses are disproved. During the first year of the study, five clinical sites have entered patients in the study. The complexities of the protocol have resulted in fewer than expected numbers of patients being enrolled, potentially jeopardizing a major benefit of the study, namely, analysis based on a large patient study population from geographically separate sites. This specific grant proposal is to add a sixth center and investigator, with a large available patient population, excellent clinical facilities, and exerience in clinical studies of affective disorders, to reasonably insure that the initial, and still important, large sample size will be met during the period of the study.